EP1916245B1 - Indolderivat mit pgd2-rezeptor-antagonistischer wirkung - Google Patents

Indolderivat mit pgd2-rezeptor-antagonistischer wirkung Download PDF

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EP1916245B1
EP1916245B1 EP06781305A EP06781305A EP1916245B1 EP 1916245 B1 EP1916245 B1 EP 1916245B1 EP 06781305 A EP06781305 A EP 06781305A EP 06781305 A EP06781305 A EP 06781305A EP 1916245 B1 EP1916245 B1 EP 1916245B1
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Prior art keywords
optionally substituted
compound
ring
alkyloxy
hydrate
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French (fr)
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EP1916245A1 (de
EP1916245A4 (de
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Akira c/o Shionogi & Co. Ltd. KUGIMIYA
Michitaka c/o Shionogi & Co. Ltd. SHICHIJO
Yoshiharu c/o Shionogi & Co. Ltd. HIRAMATSU
Natsuki c/o Shionogi & Co. Ltd. ISHIZUKA
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Shionogi and Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to an indole derivative having DP receptor antagonistic activity and a medicinal use thereof.
  • Prostaglandin D2(PGD2) is a metabolic product of arachidonic acid through PGG2 and PGH2, and known to have various potent physiological activities.
  • PGD2 is involved in sleeping and secretion of hormones in central nervous system, and in inhibiting activity of platelet aggregation, contraction of bronchial smooth muscle, vasodilation and constriction of a blood vessel etc. in peripheral system.
  • PGD2 is considered to be involved in forming pathological condition of an allergic disease such as bronchial asthma since it is a major metabolic product of arachidonic acid produced from a mast cell, and has a potent bronchoconstricting effect, causing an increase of blood vessel permeability and migration of inflammatory cell such as an eosinophil.
  • a DP receptor also called DP1 receptor
  • CRTH2 receptor also called DP2 receptor
  • Patent literatures 1-9 indole derivatives having a DP receptor antagonistic activity is disclosed, and in Patent literatures 10-21 indole derivatives having a CRTH2 receptor antagonistic activity is disclosed
  • indole derivatives having inhibitory activity against noradrenalin re-uptake are disclosed in Patent literature 22.
  • the present invention provides an indole derivative having DP receptor antagonistic activity and a pharmaceutical composition comprising the said compound as an active ingredient.
  • the said pharmaceutical composition is useful as a therapeutic agent for treating allergic diseases.
  • the indole carboxylic acid derivative shown below has a potent DP receptor antagonistic activity and the pharmaceutical composition comprising the said compound as an active ingredient is useful as a therapeutic agent for treating allergic diseases.
  • the present invention relates to
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • a fluorine atom, a chlorine atom and a bromine atom are preferable.
  • hetero atom means an oxygen atom, a sulfur atom and a nitrogen atom.
  • alkyl means a monovalent straight or branched hydrocarbon group having one to eight carbon atom(s).
  • methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, and n-octyl are exemplified.
  • C1-C6 alkyl is preferred.
  • C1-C4 alkyl is further preferred.
  • alkenyl means a monovalent straight or branched hydrocarbon group having two to eight carbon atoms and one or more double bond(s).
  • vinyl, allyl, 1-propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-heptenyl, and 2-octenyl are exemplified.
  • C2-C6 alkenyl is preferred.
  • C2-C4 alkenyl is further preferred.
  • alkynyl means a monovalent straight or branched hydrocarbon group having two to eight carbon atoms and one or more triple bond(s).
  • alkynyl a monovalent straight or branched hydrocarbon group having two to eight carbon atoms and one or more triple bond(s).
  • ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-hexynyl, 2-heptynyl, and 2-octynyl are exemplified.
  • C2-C6 alkynyl is preferred.
  • C2-C4 alkynyl is further preferred.
  • cycloalkyl means a cycloalkyl having three to eight carbon atoms and for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl are exemplified. C3-C6 cycloalkyl is preferred.
  • cycloalkenyl means a cycloalkenyl having three to eight carbon atoms and for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cycloocentyl are exemplified.
  • C3-C6 cycloalkenyl is preferred.
  • alkyloxy means a group wherein an oxygen atom is substituted with one "alkyl” above and for example, methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, 2-pentyloxy, 3-pentyloxy, n-hexyloxy, isohexyloxy, 2-hexyloxy, 3-hexyloxy, n-heptyloxy, and n-octyloxy are exemplified.
  • C1-C6 alkyloxy is preferred.
  • C1-C4 alkyloxy is further preferred. When a number of carbon is specified, it means “alkyloxy" having the carbon number within the range.
  • alkenyloxy means a group wherein an oxygen atom is substituted with one "alkenyl” above and for example, vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, and 2-octenyloxy are exemplified.
  • C2-C6 alkenyloxy is preferred.
  • C2-C4 alkenyloxy is further preferred.
  • a number of carbon it means “alkenyloxy" having the carbon number within the range.
  • alkynyloxy means a group wherein an oxygen atom is substituted with one "alkynyl" above and for example, ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, and 2-octynyloxy are exemplified.
  • C2-C6 alkynyloxy is preferred.
  • C2-C4 alkynyloxy is further preferred.
  • cycloalkyloxy means a group wherein an oxygen atom is substituted with one "cycloalkyl" above and for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy are exemplified.
  • C3-C6 cycloalkyloxy is preferred.
  • a number of carbon it means “cycloalkyloxy" having the carbon number within the range.
  • cycloalkenyloxy means a group wherein an oxygen atom is substituted with one "cycloalkenyl" above and for example, cyclopropenyloxy, ctclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy, and cyclooctenyloxy are exemplified.
  • C3-C6 cycloalkenyloxy is preferred.
  • a number of carbon it means “cycloalkenyloxy" having the carbon number within the range.
  • alkylthio means a group wherein a sulfur atom is substituted with one "alkyl” above, and for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, 2-pentylthio, 3-pentylthio, n-hexylthio, isohexylthio, 2-hexylthio, 3-hexylthio, n-heptylthio, and n-octylthio are exemplified.
  • C1-C6 Alkylthio is preferred.
  • C1-C4 alkylthio is more preferred. When a number of carbon is specified, it means "alkylthio" having the
  • alkynylthio means a group wherein a sulfur atom is substituted with one "alkynyl" above and for example, ethynylthio, 1-propynylthio, 2-propynylthio, 2-butynylthio, 2-pentynylthio, 2-hexynylthio, 2-heptynylthio, and 2-octynylthio are exemplified. C2-C6 alkynylthio is preferred. Moreover, C2-C4 alkynylthio is further preferred. When a number of carbon is specified, it means “alkynylthio" having the carbon number within the range.
  • alkylsulfinyl means a group wherein sulfinyl is substituted with one "alkyl” above and for example, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl, isopentylsulfinyl, 2-pentylsulfinyl, 3-pentylsulfinyl, n-hexylsulfinyl, isohexylsulfinyl, 2-hexylsulfinyl, 3-hexylsulfinyl, n-heptylsul
  • alkylsulfonyl means a group wherein sulfonyl is substituted with one "alkyl” above and for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, 2-pentylsulfonyl, 3-pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, 2-hexylsulfonyl, 3-hexylsulfonyl, n-heptylsul
  • alkylsulfonyloxy means a group wherein an oxygen atom is substituted with one "alkylsulfonyl" above and for example, methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonytoxy, isopropylsulfonyloxy, n-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, n-pentylsulfonyloxy, isopentylsulfonyloxy, 2-pentylsulfonyloxy, 3-pentylsulfonyloxy, n-hexylsulfonyloxy, isohexylsulfonyloxy, 2-hexylsulfonyloxy, 3-hexylsulfonyloxy
  • cycloalkylthio means a group wherein a sulfur atom is substituted with one "cycloalkyl" above and for example, cyclopropylthio, cyclobutylthio, cyclopantylthio, cyclohexylthio, cycloheptylthio and cyclooctylthio are exemplified.
  • C3-C6 cycloalkylthio is preferred.
  • a number of carbon it means “cycloalkylthio" having the carbon number within the range.
  • cycloalkylsulfinyl includes a substituent group in which sulfinyl is substituted with one "cycloalkyl” described above.
  • cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cycloheptylsulfinyl, and cyclooctylsulfinyl are exemplified.
  • C3-C6 cycloalkylsulfinyl is exemplified.
  • cycloalkylsulfonyl includes a substituent group in which sulfonyl is substituted with one "cycloalkyl” described above.
  • cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl, and cyclooctylsulfonyl are exemplified.
  • C3-C6 cycloalkylsulfonyl is exemplified.
  • cycloalkylsulfonyloxy includes a substituent group in which an oxygen atom is substituted with one "cycloalkylsulfonyl" described above.
  • cyclopropylsulfonyloxy, cyclobutylsulfonyloxy, cyclopentylsulfonyloxy, cyclohexylsulfonyloxy, cycloheptylsulfonyloxy, and cyclooctylsulfonyloxy are exemplified.
  • C3-C6 cycloalkylsulfonyloxy is exemplified.
  • cycloalkenylthio includes a substituent group in which a sulfur atom is substituted with one "cycloalkenyl” described above.
  • cyclopropenylthio, cyclobutenylthio, cyclopentenylthio, cyclohexenylthio, cycloheptenylthio, and cyclooctenylthio are exemplified.
  • C3-C6 cycloalkenylthio is exemplified.
  • a number of carbon it means “cycloalkenylthio" having the carbon number within the range.
  • cycloalkenylsulfinyl includes a substituent group in which sulfinyl is substituted with one "cycloalkenyl” described above.
  • cyclopropenylsulfinyl, cyclobutenylsulfinyl, cyclopentenylsulfinyl, cyclohexenylsulfinyl, cycloheptenylsulfinyl, and cyclooctenylsulfinyl are exemplified.
  • C3-C6 cycloalkenylsulfinyl is exemplified.
  • cycloalkenylsulfonyl includes a substituent group in which sulfonyl is substituted with one "cycloalkenyl” described above.
  • cyclopropenylsulfonyl, cyclobutenylsulfonyl, cyclopentenylsulfonyl, cyclohexenylsulfonyl, cycloheptenylsulfonyl, and cyclooctenylsulfonyl are exemplified.
  • C3-C6 cycloalkenylsulfonyl is exemplified.
  • cycloalkenylsulfonyloxy includes a substituent group in which an oxygen atom is substituted with one "cycloalkenylsulfonyl" described above.
  • cyclopropenylsulfonyloxy, cyclobutenylsulfonyloxy, cyclopentenylsulfonyloxy, cyclohexenylsulfonyloxy, cycloheptenylsulfonyloxy, and cyclooctenylsulfonyloxy are exemplified.
  • C3-C6 cycloalkenylsulfonyloxy is exemplified.
  • alkyloxycarbonyl includes a substituent group in which carbonyl is substituted with one "alkyloxy” described above.
  • methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl and n-pentyloxycarbonyl are exemplified.
  • C1-C4 alkyloxycarbonyl is exemplified.
  • C1-C2 alkyloxycarbonyl is further preferable.
  • alkenyloxycarbonyl includes a substituent group in which carbonyl is substituted with one "alkenyloxy” described above.
  • vinyloxycarbonyl, allyloxycarbonyl, 1-propenyloxycarbonyl, and 2-pentenyloxyarbonyl are exemplified.
  • C2-C4 alkyloxycarbonyl is exemplified.
  • alkynyloxycarbonyl includes a substituent group in which carbonyl is substituted with one "alkynyloxy” described above.
  • alkynyloxycarbonyl ethynyloxycarbonyl, 1-propynyloxycarbonyl, 2-propynyloxycarbonyl, 2-butynyloxyarbonyl and 2-pentynyloxycarbonyl are exemplified.
  • C2-C4 alkynyloxycarbonyl is exemplified.
  • acyl includes alkylcarbonyl wherein the part of alkyl is “alkyl” described before, alkenylcarbonyl wherein the part of alkenyl is “alkenyl” described before, alkynylcarbonyl wherein the part of alkynyl is “alkynyl” described before, cycloalkylcarbonyl wherein the part of cycloalkyl is “cycloalkyl” described before, arylcarbonyl wherein the part of aryl is “aryl” described below, heteroarylcarbonyl wherein the part of heteroaryl is “heteroaryl” described below and non-aromatic heterocycliccarbonyl wherein the part of non-aromatic heterocyclic group is "non-aromatic heterocyclic group” described below.
  • alkenyl alkynyl
  • cycloalkyl aryl
  • heteroaryl heteroaryl
  • non-aromatic heterocyclic may be substituted respectively with substituent groups exemplified in "optionally substituted alkyl”, “optionally substituted alkenyl”, “optionally substituted alkynyl”, “optionally substituted cycloalkyl”, “optionally substituted aryl”, “optionally substituted heteroaryl” and “optionally substituted non-aromatic heterocyclic group” described below.
  • the acyl group include acetyl, propionyl, butyroyl, cyclohexylcarbonyl, benzoyl, and pyridinecarbonyl.
  • a term of “optionally substituted amino” includes an amino group which may be substituted with one or two group(s) of "alkyl” before, “alkenyl” before, “alkynyl” before, “cycloalkyl” before, “cycloalkenyl” before, “aryl” below, “heteroaryl” below, “acyl” before, “alkyloxycarbonyl” before, “alkenyloxycarbonyl” before, “alkynyloxycarbonyl” before, “alkylsulfonyl”, “alkenylsulfonyl”, “alkynylsulfonyl”, “arylsulfonyl” and/or “heteroarylsulfonyl” before.
  • Examples of the optionally substituted amino group include amino, methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, benzylamino, acetylamino, benzoylamino, methyloxycarbonylamino and methanesulfonylamino.
  • amino, methylamino, dimethylamino, diethylamino, ethylmethylamino, acetylamino and methanesulfonylamino are exemplified.
  • a term of "optionally substituted carbamoyl” includes an aminocarbonyl group wherein the part of optionally substituted amino is “optionally substituted amino" described before and examples of the optionally substituted carbamoyl group includes carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-phenylcarbamoyl, N-benzylcarbamoyl, N-acetylcarbamoyl and N-methylsulfonylcarbamoyl.
  • carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl and N-methylsulfonylcarbamoyl are exemplified.
  • a term of "optionally substituted sulfamoyl” includes an aminosulfonyl group wherein the part of optionally substituted amino is “optionally substituted amino" described before and examples of the optionally substituted sulfamoyl group include sulfamoyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl, N-ethyl-N-methylsulfamoyl, N,N-diethylsulfamoyl, N-phenylsulfamoyl, N-benzylsulfamoyl, N-acetylsulfamoyl and N-methylsulfonylsulfamoyl.
  • sulfamoyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl and N-methylsulfonylsulfamoyl are exedoyl, N
  • alkylene includes a straight or branched alkylene group having one to eight carbon atom(s) and for example, methylene, ethylene, 1-methylethylene, trimethylene, 1-methyltrimethylene, pentamethylene, and hexamethylene are exemplified.
  • C1-C4 alkylene is preferred.
  • C1-C2 alkylene is further preferred.
  • aryl includes a monocyclic or fused cyclic aromatic hydrocarbons and it may be fused with "cycloalkyl” before, “cycloalkenyl” before or “non-aromatic heterocyclic group” below at any possible position. Both of monocyclic ring and fused ring may be substituted at any position and for example, phenyl, 1-naphthyl, 2-naphthyl, anthryl, tetrahydronaphthyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl are exemplified. Phenyl, 1-naphthyl and 2-naphthyl are preferred. Moreover, phenyl is further preferred.
  • non-aromatic heterocyclic group in R 1 , R 2 , R 3 , R 4 and R 5 includes a 5- to 7-membered non-aromatic heterocyclic ring containing one or more of heteroatom(s) selected independently from oxygen, sulfur and nitrogen atoms or a multicyclic ring formed by fusing the two or more rings thereof.
  • pyrrolidinyl e.g., 1-pyrrolidinyl, 2-pyrrolidinyl
  • imidazolidinyl e.g., 2-imidazolidinyl
  • imidazolinyl e.g., imidazolinyl
  • pyrazolidinyl e.g., 1- pyrazolidinyl, 2-pyrazolidinyl
  • pyrazolinyl e.g., pyrazolinyl
  • piperadinyl e.g., 1-piperadinyl
  • indolinyl e.g., 1-indolinyl
  • morpholinyl e.g., morpholino, 3-morpholinyl
  • non-aromatic heterocyclic group in R 1 , R 8 , R 10 , R 11 , R 13 and R 14 includes a 5- to 7-membered non-aromatic heterocyclic ring containing one or more of heteroatom(s) selected independently from oxygen, sulfur and nitrogen atoms or a multicyclic ring formed by fusing the two or more rings thereof.
  • pyrrolidinyl e.g., 1-pyrrolidinyl, 2-pyrrolidinyl
  • piperidyl e.g., piperidino, 2-piperidyl
  • piperadinyl e.g., 1-piperadinyl
  • morpholinyl e.g., morpholino, 3-morpholinyl
  • heteroaryl in R 1 , R 2 , R 3 , R 4 and R 5 includes a 5- to 6-membered aromatic ring containing one or more of heteroatom(s) selected independently from oxygen, sulfur and nitrogen atoms and it may be fused with "cycloalkyl” before, “aryl” before, “non-aromatic heterocyclic group” or other heteroaryl at any possible position.
  • the heteroaryl group may be substituted at any position whenever it is a monocyclic ring or a fused ring.
  • pyrrolyl e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl
  • furyl e.g., 2-furyl, 3-furyl
  • thienyl e.g., 2-thienyl, 3-thienyl
  • imidazolyl e.g.” 2-imidazolyl, 4-imidazolyl
  • pyrazolyl e.g., 1-pyrazolyl, 3-pyrazolyl
  • isothiazolyl e.g., 3-isothiazolyl
  • oxazolyl e.g., 2-oxazolyl
  • thiazolyl e.g., 2-thiazolyl
  • pyridyl e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrazinyl e.g., 2-pyrazinyl
  • heteroaryl in R 7 , R 8 , R 10 , R 11 , R 13 and R 14 includes a 5- to 6-membered aromatic ring containing one or more of heteroatom(s) selected independently fromoxygen, sulfur and nitrogen atoms and it may be fused with "cycloalkyl” before, “aryl” before, “non-aromatic heterocyclic group” before or other heteroaryl at any possible position.
  • the heteroaryl group may be substituted at any position whenever it is monocyclic or fused ring.
  • furyl e.g., 2-furyl, 3-furyl
  • thienyl e.g., 2-thienyl, 3-thienyl
  • imidazolyl e.g., 2-imidazolyl, 4-imidazolyl
  • pyrazolyl e.g., 1-pyrazolyl, 3-pyrazolyl
  • isothiazolyl e.g., 3-isothiazolyl
  • oxazolyl e.g., 2-oxazolyl
  • thiazolyl e.g., 2-thiazolyl
  • pyridyl e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrazinyl e.g., 2-pyrazinyl
  • pyrimidinyl e.g., 2-pyrimidinyl, 4-pyrimidinyl
  • aryloxy includes a substituent group in which an oxygen atom is substituted with one "aryl” before and for example, phenyloxy and naphthyloxy are exemplified.
  • arylthio includes a substituent group in which a sulfur atom is substituted with one "aryl” before and for example, phenylthio and naphthylthio are exemplified.
  • arylsulfinyl includes a substituent group in which sulfinyl is substituted with one "aryl” before and for example, phenylsulfinyl and naphthylsulfinyl are exemplified.
  • arylsulfonyl includes a substituent group in which sulfonyl is substituted with one "aryl” before and for example, phenylsulfonyl and naphthylsulfoinyl are exemplified.
  • arylsulfonyloxy examples include phenylsulfonyloxy and naphthylsulfonyloxy.
  • heteroaryloxy includes a substituent group in which an oxygen atom is substituted with one "heteroaryl” before.
  • furyloxy, thienyloxy, imidazolyloxy, pyrazolyloxy, isothiazolyloxy, isoxazolyloxy, oxazolyloxy, thiazolyloxy, pyridyloxy, pyrazinyloxy, pyrimidinyloxy and pyridazinyloxy are exemplified
  • heteroarylthio includes a substituent group in which a sulfur atom is substituted with one "heteroaryl” before.
  • furylthio, thienylthio, imidazolylthio, pyrazolylthio, isothiazolylthio, isoxazolylthio, oxazolylthio, thiazolylthio, pyridylthio, pyrazinylthio, pyrimidinylthio, and pyridazinylthio are exemplified.
  • heteroarylsulfinyl includes a substituent group in which sulfinyl is substituted with one "heteroaryl” before.
  • heteroarylsulfonyl includes a substituent group in which sulfonyl is substituted with one "heteroaryl” before.
  • furylsulfonyl, thienylsulfonyl, imidazolylsulfonyl, pyrazolylsulfonyl, isothiazolylsulfonyl, isoxazolylsulfonyl, oxazolylsulfonyl, thiazolylsulfonyl, pyridylsulfonyl, pyrazinylsulfonyl, pyrimidinylsulfonyl and pyridazinylsulfonyl are exemplified.
  • heteroarylsulfonyloxy includes a substituent group in which an oxygen atom is substituted with one "heteroarylsulfonyl” before.
  • aromatic carbocyclic ring includes an aromatic monocyclic or fused carbocyclic ring and for example, a benzene ring, a naphthalene ring and an anthracene ring are exemplified.
  • a benzene ring is preferred.
  • aromatic heterocyclic ring includes an aromatic monocyclic or fused heterocyclic ring.
  • C1-C6 alkylene includes a straight or branched alkylene group having one to six carbon atoms, and for example, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - are exemplified.
  • -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 - are exemplified.
  • -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -OCH 2 CH 2 O-, -OCH 2 O- and -N(CH 3 )CH 2 CH 2 CH 2 - are exemplified.
  • alkynylene optionally containing one or two heteroatom(s) includes a straight or branched alkynylene group having two to six carbon atoms, optionally containing one or two heteroatom(s) which may be substituted with "alkyl” above, and for example, -C ⁇ CCH 2 -, -CH 2 C ⁇ CH 2 -, -CH 2 C ⁇ CH 2 O-, -OCH 2 C ⁇ CH-, -CH 2 C ⁇ CH 2 S-, -SCH 2 C ⁇ CH-, -CH 2 C ⁇ CH 2 NH-, -NHCH 2 C ⁇ CH-, -CH Z C ⁇ CCH 2 N(CH 3 )- and -N(CH 3 )CH 2 C ⁇ CH- are exemplified. Especially, -CH 2 C ⁇ CCH 2 - and -OCH 2 C ⁇ CH- are preferred.
  • examples of "3- to 8-membered nitrogen-containing non-aromatic heterocyclic ring” includes rings shown in the formula of
  • a term of "3- to 8-membered nitrogen-containing heteroaromatic ring” includes a 3- to 8-membered heteroaromatic ring containing one or more of nitrogen atom(s), and further optionally an oxygen atom and/or sulfur atom in the ring.
  • pyrrolyl e.g., 1- pyrrolyl, 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl e.g., 2-imidazolyl, 4-imidazolyl
  • pyrazolyl e.g., 1-pyrazolyl, 3-pyrazolyl
  • isoxazolyl e.g., 3-isoxazolyl
  • oxazolyl e.g., 2-oxazolyl
  • thiazolyl e.g., 2-thiazolyl
  • pyridyl e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrazinyl e.g., 2-pyrazinyl
  • pyrimidinyl e.g., 2-pyrimidinyl, 4-pyrimidinyl
  • pyridazinyl e.g., 3-
  • examples of "5- or 6-membered nitrogen-containing heteroaromatic ring containing only one nitrogen atom as a heteroatom” includes rings shown in the formula of
  • substituents in “optionally substituted alkyl”, “optionally substituted alkyloxy”, “optionally substituted alkylthio”, “optionally substituted alkylsulfinyl”, “optionally substituted alkylsulfonyl”, “optionally substituted alkylsulfonyloxy” and “the optionally substituted alkyloxycarbonyl” include cycloalkyl, alkylene optionally containing one or two heteroatom(s), hydroxy, oxo, alkyloxy optionally substituted with a substituent group A at one to three position(s), mercapto, alkylthio, halogen atom, nitro, cyano, carboxy, alkyloxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, acyl, aryl optionally substituted with a substituent group B at one to three position(s) (e.g., phenyl), heteroaryl optionally substituted with a substituent group
  • substituents in “optionally substituted aryl”, “optionally substituted phenoxy”, “optionally substituted aryloxy”, “optionally substituted phenylthio”, “optionally substituted arylthio”, “optionally substituted arylsulfinyl”, “optionally substituted arylsulfonyl”, “optionally substituted arylsulfonyloxy”, “optionally substituted heteroaryl”, “optionally substituted heteroaryloxy”, “optionally substituted heteroarylthio”” “optionally substituted heteroarylsulfinyl", “optionally substituted heteroarylsulfonyl”, “optionally substituted heteroarylsulfonyloxy” and “optionally substituted non-aromatic heterocyclic group” include alkyl optionally substituted with a substituent group D at one to three position(s), cycloalkyl, alkenyl, alkynyl, hydroxy, alkyloxy optionally substituted with
  • Substituent group A is a group of a halogen atom and phenyl optionally substituted with one to three substituent(s) selected from the Substituent group B.
  • Substituent group B is a group of a halogen atom, alkyl, alkyloxy, cyano and nitro.
  • Substituent group C is a group of a halogen atom and alkyl.
  • Substituent group D is a group of a halogen atom and alkyloxy.
  • a term of "carboxy equivalent” means a biological equivalent and includes substituents having the same polar effect as a carboxy group.
  • -CONHOt-Bu -CONHOCH 2 Ph, -SO 3 H, -CONHSO 2 Ph, -SO 2 NHCOMe, -SO 2 NHCOPh, and the formulae of; are exemplified.
  • the ring A is (Ia) a benzene ring.
  • the ring B is (Id) a ring of the formula: (Ie) the formula of is more preferable, and further (If) the formula of: is most preferable.
  • R 1 , R 2 , R 4 and R 5 wherein each substituent is independent, (Ig) a hydrogen atom, a halogen atom, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino, cyano, nitro, optionally substituted aryl or optionally substituted heteroaryl is preferable, (Ih) a hydrogen atom, a halogen atom or optionally substituted alkyl is more preferable and (Ii) a hydrogen atom is most preferable.
  • R 3 (Ij) a hydrogen atom, a halogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkyloxy, optionally substituted amino, optionally substituted carbamoyl, optionally substituted aryl, optionally substituted heteroaryl or non-aromatic heterocyclic group is preferable, (Ik) a halogen atom, optionally substituted amino, optionally substituted carbamoyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted non-aromatic heterocyclic group is more preferable and (I1) a halogen atom, optionally substituted heteroaryl or optionally substituted non-aromatic heterocyclic group is most preferable.
  • R 6 (Im) C2-C6 alkyloxy, substituted C1-C6 alkyloxy, C2-C6 alkylthio or substituted C1-C6 alkylthio is preferable, (In) C2-C4 alkyloxy or C2-C4 alkylthio is more preferable and (Io) C2-C4 alkyloxy is most preferable.
  • R 7 (Ip) a halogen atom, optionally substituted alkyl, optionally substituted alkyloxy, cyano, nitro, optionally substituted aryl or optionally substituted heteroaryl is preferable, (Iq) a halogen atom, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted aryl or optionally substituted heteroaryl is more preferable, and (Ir) a halogen atom, optionally substituted alkyl or optionally substituted alkyloxy is most preferable.
  • R 8 (Is) optionally substituted alkyl or oxo is preferable, and (It) alkyl is more preferable.
  • R 9 (Iu) carboxy or carboxy-equivalent is preferable, and (Iv) carboxy is more preferable.
  • L 3 is (IIe) optionally substituted alkylene wherein one or two heteroatom may be included.
  • the ring C is (Id) above. (Ie) above is more preferable and (If) above is most preferable.
  • R 1 , R 2 , R 4 and R 5 wherein all substituents are independent (Ig) above is preferable, (Ih) above is more preferable and (Ii) above is most preferable.
  • L 4 is (IIe) above. (IIf) above is more preferable and (IIg) above is most preferable.
  • the compounds of the present invention are useful as a therapeutic agent, especially for treating allergic diseases, since they have an excellent DP receptor antagonistic activity and high safety.
  • the compounds of the present invention can be prepared by the method A or B shown below according to methods described in Tetrahedron, Vol.57, pp.2039-2049 (2001 ) and WO 2003/097598 .
  • a racemate or an optical isomer is included in chemical structures shown by the general formulae (I) to (IX); wherein the ring A and B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and L 3 have the same meanings as 1) before; the ring C, R 12 , R 13 , R 14 , L 4 and Z have the same meanings as 3) before; and Hal is a halogen atom or alkylsulfonyloxy.
  • Step 1 is a process in which the compound of the formula (III) is condensed with the compound of the formula (IV) to give the compound of the formula (V).
  • the reaction can be carried out in an inert solvent reacting one to five equivalent(s) of the compound (IV) compared to the compound (III) at 0°C to 80°C for 5 minutes to 48 hours.
  • the reaction may be carried out under the presence of one to five equivalent(s) of a base.
  • a base examples include triethylamine, pyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, and sodium hydroxide.
  • the preferable inert solvent examples include pyridine, acetonitrile, methylenechloride, and tetrahydrofuran. These can be used alone or as a mixed solvent containing water.
  • Step 2 is a process in which the compound of the formula (V) is condensed with the compound of the formula (VI), and then the product is hydrolyzed to give the compound of the formula (I).
  • the condensation reaction can be carried out in an inert solvent under a presence of a base reacting one to five equivalent(s) of the compound (IV) compared to the compound (III) at 0°C to 100°C for 5 minutes to 48 hours.
  • Examples of the preferable bases include sodium hydride, potassium hydride, potassium tert-butoxide, and potassium carbonate.
  • One to five equivalent(s) of the base compared to the compound (VI) can be used.
  • phase transfer catalyst such as tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltriethylammonium chloride and benzyltributylammonium chloride may be used.
  • the preferable inert solvent examples include pyridine, acetonitrile, methylene chloride, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, acetone, methylethylketone, and methylisobutylketone. These can be used alone or as a mixed solvent containing water.
  • the hydrolysis reaction can be carried out by using one to five equivalent(s) of the base compared to the compound (VI) in an inert solvent at 0°C to 100°C for 5 minutes to 48 hours.
  • Examples of the preferable base include sodium hydroxide and potassium hydroxide.
  • the preferable inert solvent examples include methanol and tetrahydrofuran and these can be used alone or as a mixed solvent containing water.
  • the compound (II) can be prepared from the compound (VII) through the step 1 and 2 in the same manner; wherein the ring A and B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and L 3 have the same meaning as 1) before; the ring C, R 12 , R 13 , R 14 , L 4 and Z have the same meanings as 3) before ; Hal is a halogen atom or alkylsulfonyloxy and Q is a protecting group.
  • Step 1 is a process in which the compound of the formula (VIII) is prepared by protecting the amino group of the compound of the formula (III).
  • the amino group may be protected by a t-butoxycarbonyl, benzyloxycarbonyl or allyloxycarbonyl group described in PROTECTIVE GROUP IN ORGANIC SYNTHSIS, JOHN WILEY & SONS, INC for example.
  • Step 2 is a process in which the compound of the formula (IX) is prepared by deprotecting the product after reacting the compound of the formula (VIII) with the compound of the formula (VI).
  • the condensation reaction can be carried out in an inert solvent reacting one to five equivalent(s) of the compound (IV) compared to the compound (III) at 0°C to 100°C for 5 minutes to 48 hours.
  • Examples of the preferable base include sodium hydride, potassium hydride, potassium t-butoxide, and potassium carbonate.
  • One to five equivalent(s) of the base compared to the compound (VI) can be used.
  • phase transfer catalyst such as tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltriethylammonium chloride and benzyltributylammonium chloride may be used.
  • the preferable inert solvent examples include pyridine, acetonitrile, methylene chloride, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, acetone, methylethylketone, and methylisobutylketone. These can be used alone or as a mixed solvent containing water.
  • the protecting group, Q is removed under conventional deprotecting conditions.
  • Step 2 is a process in which the compound of the formula (I) is prepared by hydrolyzing the product after reacting the compound of the formula (IX) with the compound of the formula (IV).
  • the condensation reaction can be carried out in an inert solvent reacting one to five equivalent(s) of the compound (IV) compared to the compound (IX) at 0°C to 100°C for 5 minutes to 48 hours.
  • the reaction may be carried out under the presence of one to five equivalent(s) of a base.
  • a base examples include triethylamine, pyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, and sodium hydroxide.
  • Examples of the preferable inert solvent include pyridine, acetonitrile, methylene chloride, and tetrahydrofuran.
  • the hydrolysis reaction can be carried out in an inert solvent using one to five equivalent(s) of a base compared to the compound (IX) at 0°C to 100°C for 5 minutes to 48 hours.
  • Examples of the preferable base include sodium hydroxide and potassium hydroxide.
  • the preferable inert solvent examples include methanol and tetrahydrofuran, which is can be used alone or as a mixed solvent with water.
  • the compound of the formula (VII) can be prepared from the compound (VII) through the step 1 to 3 in the same manner.
  • solvate includes, for example, a solvate with an organic solvent, a hydrate and the like.
  • any number of molecules of the organic solvent may coordinated.
  • any number of water molecules may be coordinated.
  • a hydrate is usually preferred.
  • a term of "compound of the present invention” includes a pharmaceutically acceptable salt and a solvate thereof.
  • the salt include salts with alkaline metal (e.g. lithium, sodium and potassium), alkaline earth metal (e.g. magnesium and calcium), ammonium, organic bases and amino acids and salts with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid) and organic acids (e.g. acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid and p-toluenesulfonic acid).
  • alkaline metal e.g. lithium, sodium and potassium
  • alkaline earth metal e.g. magnesium and calcium
  • ammonium organic bases and amino acids
  • organic bases and amino acids e.g. hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid
  • organic acids e.g. acetic acid, citric acid, maleic acid, fumaric acid,
  • a compound of the present invention is not limited to the specified isomer but includes all possible isomers and racemates.
  • a compound of the present invention shows an excellent DP receptor antagonistic activity as described in the following examples.
  • a pharmaceutical composition of the present invention can be used as a therapeutic agent for preventing and/or treating, for example, allergic diseases such as asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, and food allergy; systemic mastocytosis; systemic disorder of mastcell-activation; lung emphysema; chronic bronchitis; chronic obstructive lung disease; skin disorder characterized by pruritus such as atopic dermatitis and hives; diseases occuring secondarily due to behavior accompanied by pruritus such as cataract and retinal detachment; brain damages such as cerebrovascular disorder, degenerative brain disorder and demyelinating disease; sleep-waking disorder; Churg-Strauss syndrome; papular dermatitis such as filariasis; vasculitis; polyarteritis; cutaneous eosoiophilic granuloma;
  • a compound of the present invention When a compound of the present invention is administered to a human in order to treat the diseases above, oral administration through, for example, a powder, granule, tablet capsule, pill, or liquid formulation, or parenteral administration through an injection, suppository, transdermal formulation, or inhalant is possible.
  • a pharmaceutical composition can be obtained by mixing a therapeutically effective amount of a compound of the present invention with a pharmaceutical additive such as an excipient, binder, wetting agent, disintegrating agent, or lubricant, which is suitable to the selected formulation.
  • a pharmaceutical additive such as an excipient, binder, wetting agent, disintegrating agent, or lubricant, which is suitable to the selected formulation.
  • An injection can be formulated by sterilization together with a suitable carrier.
  • the compound of the present invention can be used combined with or in a coupled formulation with the other therapeutic agent.
  • the compound can be used combined with or in a coupled formulation with leukotriene receptor antagonist(e.g., montelukast sodium, zafirlukast, pranlukast hydrate, leukotriene B4 receptor antagonist); leukotriene synthesis inhibitor such as zileuton, PDE IV inhibitor(e.g., theophylline, cilomilast, roflumilast), corticosteroid(e.g., prednisolone, fluticasone, budesonide, ciclesonide), 2-agonist(e.g., salbutamol, salmeterol, formoterol), anti IgE antagonist(e.g., omalizumab), histamine H1 receptor antagonist(e.g., chlorpheniramine, lorat
  • antitussive agent e.g., codein, hydrocodein
  • cholesterol lowering agent lovastatin, simvastatin, fluvastatin, rosuvastatin
  • anticholinergic drug e.g., tiotropium, ipratropium, flutropium, oxitropium
  • Dose of the compounds of the present invention depends on condition of diseases, route of administration, age and body weight of a patient. In the case of oral administration to an adult, the dose range is usually 0.1 to 100 mg/kg/day, preferably 1 to 20 mg/kg/day.
  • Triethylamine(11-8 ⁇ L, 0.84 mmol) and 4-isopropyloxybenzenesulfonyl chloride(104 mg, 0.44 mmol) were added to a solution of the compound(1) (93 mg, 0.42 mmol) in THF(2 mL) and the solution was stirred at room temperature for 1.5 hours.
  • the solution was diluted with water, extracted with ethyl acetate, and the organic layer was washed with diluted hydrochloric acid and water successively, dried and concentrated.
  • Trifluoroacetic acid(1.0 mL) was added to a solution of the compound (4) (183 mg, 0.303 mmol) obtained in the first step in methylene chloride(1.0 mL) and the solution was stirred at room temperature for 4 hours.
  • the reaction solution was concentrated in vacuo and the resulting crude crystalline was recrystalized from ethanol to give the compound I-81(78 mg, 47 %).
  • Test Example 1 DP inhibitory activity in vitro
  • peripheral blood 30 ml of peripheral blood was collected from a healthy volunteer using a syringe containing one ninth amount of 3.8 % sodium citrate for diagnosis. After being centrifuged at 180 g for 10 minutes at room temperature, a supernatant was collected and used as Platelet Rich Plasma(PRP). The resulting PRP was washed with wash buffer and centrifuged three times(Washed Platelet: WP) and platelets were counted by a microcell counter. WP was added to a plate in amount of 1.5 x 10 8 /assay and the plate was treated with 3-isobutyl-1-methylxanthin(IBMX; 0.5 mM) for 5 minutes.
  • IBMX 3-isobutyl-1-methylxanthin
  • a reaction was initiated by adding 100 nM of PGD 2 5 min after an addition of a test compound. The reaction was terminated with an addition of 1N HCl after 2 minutes and the cells were destructed using 12 % triton X-100. An amount of cAMP in the supernatant was assayed by Homogeneous Trangient Fluorescence(HTRF)
  • a prepared WP was homogenated and a membrane fraction was collected with high-speed centrifugation.
  • a compound of the present invention or a reference compound A(No. IC-73 in WO 2003/097598 ) was added to the plate and [ 3 H]-PGD 2 was also added.
  • a platelet membrane, a protein concentration is 2 mg/mL, was added and mixed in the plate, and placed on ice for 2 hours.
  • the reaction solution was transferred to a low protein-adsorptive filter and washed with a wash solution eight times using a cell harvester. After the final washing, water was removed sufficiently, and micoscinti was added.
  • DP inhibitory activity was investigated by measuring [ 3 H] by using Micro Beta.
  • Agonistic and antagonistic activities of the compounds of the present invention were evaluated based on intracellular calcium flux or cAMP-production as an indicator using HEK 293 cells expressing human EP1, EP2, EP3, EP4, FP, TP and IP respectively. Any compounds did not show an agonistic activity against each prostanoid. In the other hand, more than twenty times potent antagonistic activity(IC 50 ) was found in every compound compared with IC 50 of cAMP assay with WP. [Table 37] No. of compounds IC50 (nM) Ki (nM) No.
  • Test Example 2 Test using OVA asthma model of rat
  • acetylcholine (3.9, 7.8, 15.6, 31.3, 62.5, 125, 250 and 500 ⁇ g/kg) was injected to jugular vein of the rats successively from a lower dose at intervals of 5 minutes three days after the fourth exposure to the antigen, and immediate contractile reaction of airways(an increase of insufflation pressure) was measured by a modified method of Konnzett & Rössler. Inhibition rate of increased hyperresponsive airway against the control group was calculated based on area under curve(AUC) obtained from concentration-response curve of acetylcholine.
  • AUC area under curve
  • bronchoalveoli of the rats were washed with 5 mL of saline three times. Total cell number in the washings was counted by a hemacytometer under light microscope, and inhibition rates of infiltration of inflammatory cells against the control group were calculated. Further, muchin in the airway lavage fluid was measured by ELIZA method using jacalin, a muchin-binding lectin, and the inhibition rates of mucus-secretion against the control group were calculated.
  • Test Example 3 Test using nasal congestion model of guinea pig
  • ovalbumin(OVA) A 1% solution of ovalbumin(OVA) was aerosolized by ultrasonic nebulizer, a male Hartley guinea pigs was sensitized by inhalation of the aerosol for 10 minutes twice at an interval of a week and a reaction was initiated by exposure to the antigen 7 days later.
  • Trachea of the guinea pig was incised under pentobarbital anesthesia(30 mg/kg, i.p.), and cannulae were fitted at the sides of nasal cavity and lung respectively.
  • a ventilator supplying 4 mL of air every time at a rate of 60 times/min was connected.
  • Spontaneous breathing of the guinea pig was stopped by the administration of gallamine(2 mg/kg, i.v.) and 4 mL of air every time was supplied at a rate of 70 times/minute to rostrum of nose through the cannula of the nasal side using a ventilator.
  • Air pressure necessary for supplying the air was measured by a transducer fitted at the side branch and used as an indicator for resistance of nasal cavity.
  • Exposure to the antigen was performed by generating the aerosol of 3% OVA solution between the ventilator and the nasal cavity cannula for three minutes.
  • Compounds of the present invention were administered intravenously 10 minutes before the exposure to the antigen.
  • Resistance of nasal cavity was continuously measured during a period from 0 to 30 minutes, and the inhibition rate against the vehicle was obtained based on AUC of the 30 minutes, which was recorded with resistance of nasal cavity(cm H 2 O) as a longitudinal axis, and time(from 0 to 30 min.) as an abscissa axis.
  • a term of "active ingredient” means the compounds of the present invention, pharmaceutically acceptable salt or hydrate thereof.
  • a hard-gelatin capsule is prepared with the following ingredients; Amount (mg/capsule) active ingredient 250 starch (dried) 200 magnesium stearate 10 Total 460 mg
  • a tablet is prepared with the following ingredients; Amount (mg/tablet) active ingredient 250 cellulose(micro crystalline) 400 silicon dioxide (fume) 10 stearic acid 5 Total 665 mg The ingredients above are mixed and compressed to give a tablet weighing 665 mg/tablet.
  • the active ingredient and ethanol are mixed and the mixture is added to a part of propellant 22, and the resulting solution is transferred to a filling apparatus after being cooled to -30°C.
  • the necessary amount is provided to a stainless-steel vessel and the content is diluted with the remaining propellant.
  • a valve unit is fitted to the vessel.
  • a tablet containing 60 mg of an active ingredient is prepared as follows; active ingredient 60 mg starch 45 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone (10% aq. solution) 4 mg sodium carboxymethylstarch 4.5 mg magnesium stearate 0.5 mg talc 1 mg Total 150 mg
  • the active ingredient, starch and cellulose are put through a sieve of No. 45 mesh US and mixed sufficiently.
  • the resulting powder is mixed with a solution containing polyvinylpyrrolidone and the mixture is put through a sieve of No.14 mesh US.
  • the granulated powder is dried at 50°C and put through a sieve of No.18 mesh US.
  • Sodium carboxymethylstarch, magnesium stearate and talc are put through a sieve of No.60 mesh US in advance and added to the granulated powder, mixed and compressed by a tableting machine to give a tablet weighing 150 mg/tablet.
  • a capsule containing 80 mg of an active ingredient is prepared as follows; active ingredient 80 mg starch 59 mg microcrystalline cellulose 59 mg magnesium stearate 2 mg Total 200 mg
  • the active ingredient, starch, cellulose and magnesium stearate are mixed, put through a sieve of No.45 mesh US and filled in hard-gelatin capsules to give a capsule formulation containing 200 mg/capsule.
  • a suppository containing 225 mg of an active ingredient is prepared as follows; active ingredient 225 mg saturated fatty acid gliceride 2000 mg Total 2225 mg
  • the active ingredient is put through a sieve of No.60 mesh US and suspended in the saturated fatty acid gliceride melted by the least amount of heating. Then, the mixture was cooled in a mold of 2 g in appearance.
  • a suspension containing 50 mg of an active ingredient is prepared as follows; active ingredient 50 mg sodium carboxymethylcellulose 50 mg syrup 1.25 ml solution of benzoic acid 0.10 ml flavor q.v. pigment q.v. Total (adding purified water) 5 ml
  • the active ingredient is put through a sieve of No.45 mesh US and mixed with sodium carboxymethylcellulose and syrup to give a smooth paste.
  • the solution of benzoic acid and flavor are diluted with a part of water and added to the paste and stirred. A necessary amount of water is added to give the objective suspension.
  • a formulation for i.v. injection is prepared as follows; active ingredient 100 mg saturated fatty acid gliceride 1000 ml
  • the solution containing the active ingredient above is usually injected intravenously to a patient at a rate of 1 ml/min.

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Claims (15)

  1. Verbindung der generischen Formel (I):
    Figure imgb0279
     worin:
    der Ring A ein Benzolring ist;
    der Ring B ein Ring der Formel:
    Figure imgb0280
    Figure imgb0281
     ist;
    R1, R2, R3, R4 und R5 unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, gegebenenfalls substituiertes Alkyl, gegebenenfalls substituiertes Alkenyl, gegebenenfalls substituiertes Alkinyl, gegebenenfalls substituiertes Cyloalkyl, gegebenenfalls substituiertes Cyloalkenyl, Hydroxy, gegebenenfalls substituiertes Alkyloxy, gegebenenfalls substituiertes Alkenyloxy, gegebenenfalls substituiertes Alkinyloxy, gegebenenfalls substituiertes Cycloalkyloxy, gegebenenfalls substituiertes Cycloalkenyloxy, Mercapto, gegebenenfalls substituiertes Alkylthio, gegebenenfalls substituiertes Alkenylthio, gegebenenfalls substituiertes Alkinylthio, gegebenenfalls substituiertes Alkylsulfinyl, gegebenenfalls substituiertes Alkylsulfonyl, gegebenenfalls substituiertes Alkylsulfonyloxy, gegebenenfalls substituiertes Cycloalkylthio, gegebenenfalls substituiertes Cycloalkylsulfinyl, gegebenenfalls substituiertes Cycloalkylsulfonyl, gegebenenfalls substituiertes Cycloalkylsulfonyloxy, gegebenenfalls substituiertes Cycloalkenylthio, gegebenenfalls substituiertes Cycloalkenylsulfinyl, gegebenenfalls substituiertes Cycloalkenylsulfonyl, gegebenenfalls substituiertes Cycloalkenylsulfonyloxy, gegebenenfalls substituiertes Amino, Acyl, gegebenenfalls substituiertes Alkyloxycarbonyl, gegebenenfalls substituiertes Alkenyloxycarbonyl, gegebenenfalls substituiertes Alkinyloxycarbonyl, gegebenenfalls substituiertes Carbamoyl, gegebenenfalls substituiertes Sulfamoyl, Cyano, Nitro, gegebenenfalls substituiertes Aryl, gegebenenfalls substituiertes Aryloxy, gegebenenfalls substituiertes Arylthio, gegebenenfalls substituiertes Arylsulfinyl, gegebenenfalls substituiertes Arylsulfonyl, gegebenenfalls substituiertes Arylsulfonyloxy, gegebenenfalls substituiertes Heteroaryl, gegebenenfalls substituiertes Heteroaryloxy, gegebenenfalls substituiertes Heteroarylthio, gegebenenfalls substituiertes Heteroarylsulfinyl, gegebenenfalls substituiertes Heteroarylsulfonyl, gegebenenfalls substituiertes Heteroarylsulfonyloxy oder eine gegebenenfalls substituierte, nicht-aromatische, heterocyclische Gruppe sind;
    R6 C2-6-Alkyloxy, substituiertes C1-6-Alkyloxy, gegebenenfalls substituiertes C2-6-Alkenyloxy, gegebenenfalls substituiertes C2-6-Alkinyloxy, gegebenenfalls substituiertes C3-6-Cycloalkyloxy, gegebenenfalls substituiertes C3-6-Cycloalkenyloxy, gegebenenfalls substituiertes Aryloxy, gegebenenfalls substituiertes Heteroaryloxy, C2-6-Alkylthio, substituiertes C1-6-Alkylthio, gegebenenfalls substituiertes C2-6-Alkenylthio, gegebenenfalls substituiertes C2-6-Alkinylthio, gegebenenfalls substituiertes C3-6-Cycloalkylthio, gegebenenfalls substituiertes C3-6-Cycloalkenylthio, gegebenenfalls substituiertes Arylthio oder gegebenenfalls substituiertes Heteroarylthio ist;
    die R7 unabhängig voneinander ein Halogenatom, gegebenenfalls substituiertes Alkyl, gegebenenfalls substituiertes Alkenyl, gegebenenfalls substituiertes Alkinyl, gegebenenfalls substituiertes Cycloalkyl, gegebenenfalls substituiertes Cycloalkenyl, Hydroxy, gegebenenfalls substituiertes Alkyloxy, gegebenenfalls substituiertes Alkenyloxy, gegebenenfalls substituiertes Alkinyloxy, gegebenenfalls substituiertes Cycloalkyloxy, gegebenenfalls substituiertes Cycloalkenyloxy, Mercapto, gegebenenfalls substituiertes Alkylthio, gegebenenfalls substituiertes Alkenylthio, gegebenenfalls substituiertes Alkinylthio, gegebenenfalls substituiertes Alkylsulfinyl, gegebenenfalls substituiertes Alkylsulfonyl, gegebenenfalls substituiertes Alkylsulfonyloxy, gegebenenfalls substituiertes Cycloalkylthio, gegebenenfalls substituiertes Cycloalkylsulfinyl, gegebenenfalls substituiertes Cycloalkylsulfonyl, gegebenenfalls substituiertes Cycloalkylsulfonyloxy, gegebenenfalls substituiertes Cycloalkenylthio, gegebenenfalls substituiertes Cycloalkenylsulfinyl, gegebenenfalls substituiertes Cycloalkenylsulfonyl, gegebenenfalls substituiertes Cycloalkenylsulfonyloxy, gegebenenfalls substituiertes Amino, Acyl, gegebenenfalls substituiertes Alkyloxycarbonyl, gegebenenfalls substituiertes Alkenyloxycarbonyl, gegebenenfalls substituiertes Alkinyloxycarbonyl, gegebenenfalls substituiertes Carbamoyl, gegebenenfalls substituiertes Sulfamoyl, Cyano, Nitro, gegebenenfalls substituiertes Aryl, gegebenenfalls substituiertes Aryloxy, gegebenenfalls substituiertes Arylthio, gegebenenfalls substituiertes Arylsulfinyl, gegebenenfalls substituiertes Arylsulfonyl, gegebenenfalls substituiertes Arylsulfonyloxy, gegebenenfalls substituiertes Heteroaryl, gegebenenfalls substituiertes Heteroaryloxy, gegebenenfalls substituiertes Heteroarylthio, gegebenenfalls substituiertes Heteroarylsulfinyl, gegebenenfalls substituiertes Heteroarylsulfonyl, gegebenenfalls substituiertes Heteroarylsulfonyloxy oder eine gegebenenfalls substituierte, nicht-aromatische, heterocyclische Gruppe sind;
    die R8 unabhängig voneinander ein Halogenatom, gegebenenfalls substituiertes Alkyl, gegebenenfalls substituiertes Alkenyl, gegebenenfalls substituiertes Alkinyl, gegebenenfalls substituiertes Cycloalkyl, gegebenenfalls substituiertes Alkyloxy, Oxo, gegebenenfalls substituiertes Aryl, gegebenenfalls substituiertes Heteroaryl oder eine gegebenenfalls substituierte, nicht-aromatische, heterocyclische Gruppe sind;
    R9 Carboxy, gegebenenfalls substituiertes Alkyloxycarbonyl, gegebenenfalls substituiertes Carbamoyl oder ein Carboxyäquivalent ist, wobei das Carboxyäquivalent aus -CONHCN, -CONHOH, -CONHOMe, -CONHOt-Bu, -CONHOCH2Ph, -SO3H -SO2NH2, -SO2NHMe -NHCONH2, -NHCONMe2, -P(=O)(OH)2, -P(=O)(OH)(OEt), -P(=O)(OH)NH2, -P(=O)(OH)NHMe, -CONHSO2Ph, -SO2NHCOMe -SO2NHCOPh und einer der Formeln:
    Figure imgb0282
    Figure imgb0283
    Figure imgb0284
    Figure imgb0285
    Figure imgb0286
    Figure imgb0287
    Figure imgb0288
     ausgewählt ist;
    L3 gegebenenfalls substituiertes Alkylen ist, das ein oder zwei Heteroatom(e) enthalten kann;
    n 0, 1 oder 2 ist; und
    q 0, 1, 2 oder 3 ist;
    unter der Voraussetzung, dass R9 kein gegebenenfalls substituiertes Carbamoyl ist, wenn R1, R2, R3, R4 und R5 alle Wasserstoffatome sind;
    oder ein pharmazeutisch annehmbares Salz oder Hydrat davon.
  2. Verbindung gemäss Anspruch 1, wobei das Carboxyäquivalent aus -CONHOt-Bu, -CONHOCH2Ph, -SO3H, -CONHSO2Ph, -SO2NHCOMe, -SO2NHCOPh und einer der Formeln:
    Figure imgb0289
     und
    Figure imgb0290
     ausgewählt ist.
  3. Verbindung gemäss Anspruch 1 oder 2, wobei die Verbindung durch die generische Formel (II) dargestellt ist:
    Figure imgb0291
     worin der Ring C ein Ring der Formel:
    Figure imgb0292
    Figure imgb0293
     ist;
    R12 C2-6-Alkyloxy, substituiertes C1-6-Alkyloxy, gegebenenfalls substituiertes C2-6-Alkenyloxy, gegebenenfalls substituiertes C2-6-Alkinyloxy, gegebenenfalls substituiertes C3-6-Cycloalkyloxy, gegebenenfalls substituiertes Aryloxy, gegebenenfalls substituiertes Heteroaryloxy, C2-6-Alkylthio, substituiertes C1-6-Alkylthio, gegebenenfalls substituiertes C2-6-Alkenylthio, gegebenenfalls substituiertes C2-6-Alkinylthio, gegebenenfalls substituiertes C3-6-Cycloalkylthio, gegebenenfalls substituiertes Arylthio oder gegebenenfalls substituiertes Heteroarylthio ist;
    die R13 unabhängig voneinander ein Halogenatom, gegebenenfalls substituiertes Alkyl, gegebenenfalls substituiertes Cycloalkyl, gegebenenfalls substituiertes Amino, Acyl, gegebenenfalls substituiertes Alkyloxycarbonyl, gegebenenfalls substituiertes Carbamoyl, gegebenenfalls substituiertes Sulfamoyl, Cyano, Nitro, gegebenenfalls substituiertes Aryl, gegebenenfalls substituiertes Arylsulfonyloxy, gegebenenfalls substituiertes Heteroaryl oder eine gegebenenfalls substituierte, nicht-aromatische, heterocyclische Gruppe sind;
    die R14 unabhängig voneinander gegebenenfalls substituiertes Alkyl, gegebenenfalls substituiertes Alkenyl, gegebenenfalls substituiertes Alkinyl, Oxo, gegebenenfalls substituiertes Aryl, gegebenenfalls substituiertes Heteroaryl oder eine gegebenenfalls substituierte, nicht-aromatische, heterocyclische Gruppe sind;
    L4 gegebenenfalls substituiertes Alkylen ist, das ein oder zwei Heteroatom(e) enthalten kann;
    Z CH oder C(R13) ist; und
    q 0, 1 oder 2 ist;
    oder ein pharmazeutisch annehmbares Salz oder Hydrat davon.
  4. Verbindung gemäss Anspruch 3, worin R12 C2-6-Alkyloxy, substituiertes C1-6-Alkyloxy, C2-6-Alkylthio oder substituiertes C1-6-Alkylthio ist; oder ein pharmazeutisch annehmbares Salz oder Hydrat davon.
  5. Verbindung gemäss Anspruch 3, worin R3 ein Wasserstoffatom, ein Halogenatom, gegebenenfalls substituiertes Alkyl, gegebenenfalls substituiertes Cycloalkyl, gegebenenfalls substituiertes Alkyloxy, gegebenenfalls substituiertes Amino, gegebenenfalls substituiertes Carbamoyl, gegebenenfalls substituiertes Aryl, gegebenenfalls substituiertes Heteroaryl oder eine gegebenenfalls substituierte, nicht-aromatische, heterocyclische Gruppe ist; oder ein pharmazeutisch annehmbares Salz oder Hydrat davon.
  6. Verbindung gemäss Anspruch 3, worin R13 ein Halogenatom, gegebenenfalls substituiertes Alkyl oder gegebenenfalls substituiertes Alkyloxy ist und q 0 oder 1 ist; oder ein pharmazeutisch annehmbares Salz oder Hydrat davon.
  7. Verbindung gemäss Anspruch 3, wobei der Ring C einer der Formeln:
    Figure imgb0294
     oder
    Figure imgb0295
     ist; oder ein pharmazeutisch annehmbares Salz oder Hydrat davon.
  8. Verbindung gemäss Anspruch 3, worin n 0 ist; oder ein pharmazeutisch annehmbares Salz oder Hydrat davon.
  9. Verbindung gemäss irgendeinem der Ansprüche 3 bis 8, worin L4 gegebenenfalls substituiertes C1-6-Alkylen ist; oder ein pharmazeutisch annehmbares Salz oder Hydrat davon.
  10. Pharmazeutische Zusammensetzung, umfassend die Verbindung gemäss irgendeinem der Ansprüche 1 bis 9, oder ein pharmazeutisch annehmbares Salz oder Hydrat davon.
  11. Pharmazeutische Zusammensetzung gemäss Anspruch 10, die ein DP-Rezeptor-Antagonist ist.
  12. Pharmazeutische Zusammensetzung gemäss Anspruch 10, die ein therapeutisches Mittel gegen allergische Erkrankungen ist.
  13. Pharmazeutische Zusammensetzung gemäss Anspruch 12, wobei das therapeutische Mittel gegen allergische Erkrankungen ein Medikament gegen Asthma ist.
  14. Verbindung gemäss irgendeinem der Ansprüche 1 bis 9 oder ein pharmazeutisch annehmbares Salz oder Hydrat davon zur Verwendung bei der Behandlung von mit DP-Rezeptor in Beziehung stehenden Erkrankungen.
  15. Verbindung, ihr pharmazeutisch annehmbares Salz oder Hydrat gemäss Anspruch 14, wobei die mit dem DP-Rezeptor in Beziehung stehende Erkrankung Asthma ist.
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